Association of FHOD2 with common type 2 diabetes mellitus

Abstract

FHOD2 has been identified as a type 2 diabetes susceptibility gene. Methods for diagnosing and treating type 2 diabetes and methods for identifying compounds for use in the diagnosis and treatment of diabetes are disclosed. Improved diagnostic methods for early detection of a risk for developing type 2 diabetes mellitus in humans, and screening assays for therapeutic agents useful in the treatment of type 2 diabetes mellitus, by analyzing the FHOD2 gene or gene products from FHOD2, including variants forms of FHOD2, are disclosed. Indicators of diabetes include variant forms of the FHOD2 protein, variant forms of FHOD2 pre-mRNA or mRNA or variant forms of the genomic DNA of the FHOD2 gene or DNA surrounding FHOD2.

1 . An isolated nucleic acid comprising a polymorphic variant of SEQ ID NO: 2 wherein the polymorphic variant is associated with a metabolic disorder.  
     
     
         2 . The isolated nucleic acid of  claim 1  wherein said polymorphic variant is a single nucleotide polymorphism.  
     
     
         3 . The isolated nucleic acid sequence of  claim 1  wherein the metabolic disorder is altered glucose homeostasis.  
     
     
         4 . The isolated nucleic acid sequence of  claim 1  wherein the metabolic disorder is type 2 diabetes.  
     
     
         5 . A protein encoded by the isolated nucleic acid of  claim 1 .  
     
     
         6 . The protein of  claim 5  wherein the polymorphic variant is associated with increased risk of a type 2 diabetes.  
     
     
         7 . The protein of  claim 5  wherein the polymorphic variant is associated with increased altered glucose homeostasis.  
     
     
         8 . An antibody to the protein of  claim 5  wherein the protein varies at one amino acid.  
     
     
         9 . An antibody to the protein of  claim 5  wherein the protein is a truncated form of the protein or wherein the protein has a deletion of up to 10, 20, 30, 50 or 100 amino acids.  
     
     
         10 . An antibody to the protein of  claim 5  wherein the protein varies at two or more amino acids.  
     
     
         11 . An oligonucleotide probe comprising 20 to 100 contiguous nucleotides of a polymorphic variant of SEQ ID NO. 3 or its complement, wherein the probe is complementary to a region comprising the polymorphism and is complementary to a polymorphic variant that is associated with a metabolic disorder.  
     
     
         12 . The oligonucleotide probe of  claim 11  wherein the metabolic disorder is type 2 diabetes.  
     
     
         13 . The oligonucleotide probe of  claim 12  wherein the probe is 20 to 50 nucleotides in length.  
     
     
         14 . An oligonucleotide probe comprising 20 to 100 contiguous nucleotides of a polymorphic variant of SEQ ID NO. 2 or its complement, wherein the probe is complementary to a region comprising the polymorphism and is complementary to a polymorphic variant that is associated with a metabolic disorder.  
     
     
         15 . The oligonucleotide probe of  claim 14  wherein the metabolic disorder is type 2 diabetes.  
     
     
         16 . The oligonucleotide probe of  claim 14  wherein the probe is 20 to 50 nucleotides in length.  
     
     
         17 . The oligonucleotide probe of  claim 11  wherein the polymorphism is a haplotype tag SNP that is indicative of the presence of a haplotype that is associated with type 2 diabetes.  
     
     
         18 . A method of determining if a patient is at increase risk of developing type 2 diabetes comprising: 
 identifying a risk allele of a polymorphic variant of SEQ ID NO 2 or SEQ ID NO 3 that is associated with an increased risk of developing type 2 diabetes;    determining if the risk allele is present in the patient; and    determining that the patient is at increase risk of developing type 2 diabetes if the risk allele is present.    
     
     
         19 . The method of  claim 18  wherein said identifying step comprises: 
 resequencing at least 100,000 bases of SEQ ID NO 3 in a plurality of individuals that have type 2 diabetes;    comparing the sequences obtained to a reference sequence from a healthy individual; and    identifying at least one sequence variant that is present in at least one individual that has type 2 diabetes and absent in the reference sequence, wherein the sequence variant is indicative of a risk allele.    
     
     
         20 . The method of  claim 19  wherein at least 300,000 bases of SEQ ID NO 3 is resequenced.